The p53 protein is a cell cycle regulatory protein. It functions to inhibit the oncogenic effects of a number of oncogene proteins that induce mitosis by blocking transcription of proteins that induce mitosis and by inducing the transcription of proteins that block mitosis, and promote apoptosis. There is a correlation between the absence of the p53 protein and cell transformation and malignant disease. Haffner, R & Oren, M. (1995) Curr. Opin. Genet. Dev. 5: 84-90.
The p53 protein consists of 393 amino acids and binds to another important regulatory protein, the MDM-2 protein. HDM-2 (human double minute) and MDM-2 (mouse double minute) are p53 specific E3 ubiquitin protein ligases that suppresses the transcriptional activity of the tumor suppressor p53 and promote its degradation thereby limiting the tumor suppressor function of p53. HDM-2 and MDM-2 induce ubiquitination of p53 and target it for proteolysis in the proteasome (Alarcon-Vargas et al. 2002 Carcinogenesis 23: 541-547). Each of HDM-2 and MDM-2 have a p53 binding domain.
The MDM-gene that encodes the MDM-2 protein is a known oncogene. The MDM-2 protein forms a complex with the p53 protein, which results in the degradation of the p53 protein by a ubiquination pathway. The p53 protein binds to MDM-2 protein using an amino acid sequence that includes residues 12-29 of the p53 protein (Haffner, R & Oren, M. (1995) Curr. Opin. Genet. Dev. 5: 84-90).
Overexpression or amplification of MDM-2 (HDM-2) protein has been found in 40-60% of human malignancies, including 50% of human breast tumors. It has been suggested that the anti-tumor effect of the p53 protein might be enhanced by peptides capable of interfering with the binding of the MDM-2 protein to the p53 protein. A number of investigators have suggested that the MDM-2/p53 complex might be a target for rational drug design. See, e.g., Christine Wasylyk et al., “p53 Mediated Death of Cells Overexpressing MDM2 by an Inhibitor of MDM2 Interaction with p53”, Oncogene, 18, 1921-34 (1999), and U.S. Pat. No. 5,770,377 to Picksley et al. Cancers that have been shown to have an increased level of membrane associated HDM-2 include TUC-3 pancreatic cells, MIA-PaCa-2 human pancreatic cancer cells, MCF-7 human breast cancer cells, A-2058 human melanoma cells (Sarafraz-Yazdi, E. et al. 2010 Proc Natl Acad Sci USA 107(5): 1918-1923), K562 leukemia cells (Davitt et al. 2014 Annals of Clinical and Laboratory Science 44(3): 241-248) and primary human ovarian cancers (Sarafraz-Yazdi et al. 2015, Annals of Clinical and Laboratory Science, in press).
U.S. Pat. Nos. 8,822,419, 7,531,515, 7,883,888, 7,745,405, US 2011/0183915 and US 2014/0371156 are incorporated by reference.